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  • 1

    Stem cell research and

    therapy: an overview

    Michael S. Pepper MBChB, PhD, MD

    Institute for Cellular and Molecular Medicine

  • Overview

    Stem cell principles Therapeutic applications Stem cell legislation

  • Stem cell principles

    Stem cell differentiation potential Induced pluripotent stem cells Embryonic stem cells Somatic cell nuclear transfer Adult stem cells

  • In the beginning

    Zygote

  • In the beginning

    Zygote 8-cell embryo

  • In the beginning

    Zygote 8-cell Blastocyst embryo

  • Blastocyst

    Embryo

  • Totipotent post-fertilization to morula all the cells of the human body

    Pluripotent inner cell mass of the blastocyst cells of all three germ layers

    Multipotent hematopoietic stem cells

    neural stem cells mesenchymal stem cells

    various specialized cells in a given tissue

    Adapted from http://immunesystemimmunity.blogspot.com/2011/09/stems-cells-clinical-uses-and-potential.html

    Embryo - germ layers: mesoderm, ectoderm, endoderm

  • Induced pluripotent stem cells

    Pluripotent stem cells

    Differentiation factors

    4 transcription factors: Oct3/4

    Sox2 Klf4

    c-Myc

  • Stem cell principles

    Stem cell differentiation potential Induced pluripotent stem cells Embryonic stem cells Somatic cell nuclear transfer Adult stem cells

  • Embryonic stem cells

    Method of obtaining ES cells:

    Blastocyst 5 day old embryo approx 100 cells

    Remove inner cell mass Cultured cells = ES cells

  • Stem cell principles

    Stem cell differentiation potential Induced pluripotent stem cells Embryonic stem cells Somatic cell nuclear transfer Adult stem cells

  • Somatic (body) cell

    Nucleus introduced into egg cell

    Clone

    Egg cell

    Nucleus removed

    Somatic cell nuclear transfer

    Nucleus removed

    Adapted from http://ibiosas.wikispaces.com/Biotechnology+and+Mutations

  • Reproductive cloning

    Therapeutic cloning

    Surrogate mother

    Tissue culture

    Cloning

    Adapted from http://ibiosas.wikispaces.com/Biotechnology+and+Mutations

  • Stem cell principles

    Stem cell differentiation potential Induced pluripotent stem cells Embryonic stem cells Somatic cell nuclear transfer Adult stem cells

  • Tissue-specific adult stem cells

    bone marrow gastrointestinal tract

    liver, pancreas tooth skin, hair central nervous system kidney muscle (satellite stem cells)

  • Pluripotent vs. adult stem cells Pluripotent Differentiation potential =

    all of the body's cell types Ethical issues Technically more difficult

    to obtain Potential for

    tumorigenesis Therapeutic value

    remains to be determined Value: understanding

    disease processes, drug screening

    Adult Differentiation potential

    limited to cells of tissue in which they reside

    No ethical issues Readily available No evidence for

    tumorigenesis Therapeutic value well

    demonstrated: HSCs for bone marrow

    transplantation MSCs: approx 200 registered

    clinical trials

  • Therapeutic applications

    Source Application

  • Source

    Current Bone marrow Peripheral blood Cord blood

    Bone matrix

    Blood vessel

    Osteoblast

    Adipocyte

    Stromal cells

    Hematopoietic stem cell

    Adapted from http://stemcells.nih.gov/info/basics/basics4.asp

  • Source

    Current Bone marrow Peripheral blood Cord blood

    Bone matrix

    Blood vessel

    Osteoblast

    Adipocyte

    Stromal cells

    Hematopoietic stem cell

    http://www.newbornbabyzone.com/baby-care/caring-for-your-babys-umbilical-cord/

    Adapted from http://stemcells.nih.gov/info/basics/basics4.asp

  • Source

    Future ES cells iPS cells Adipose tissue Other

  • Source

    Future ES cells iPS cells Adipose tissue Other

  • Application

    Current Bone marrow transplantation Fractures, chronic wounds, burns

    Future Myocardial infarction and heart failure CNS disease (incl. spinal cord injury) Diabetes (beta-cells) Other

  • Bone marrow transplantation Universally employed and approved Autologous or allogeneic Indications

    - cancer - blood disorders - genetic disorders

    Adapted from http://stemcells.nih.gov/info/basics/basics4.asp

    Natural killer (NKC) cell

    T lymphocytes

    B lymphocyte

    Multipotential stem cell

    Myeloid progenitor

    cell

    Red blood cells

    Platelets

    Monocyte / macrophage

    Neutrophil

    Basophil

    Eosinophil

    Lymphoid progenitor

    cell Hematopoietic

    stem cell

  • Hematopoietic stem cell transplant indications

    Leukemias Acute Leukemia

    Acute Lymphoblastic Leukemia (ALL) Acute Myelogenous Leukemia (AML) Acute Biphenotypic Leukemia Acute Undifferentiated Leukemia Chronic Leukemia Chronic Myelogenous Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) Juvenile Chronic Myelogenous Leukemia (JCML) Juvenile Myelomonocytic Leukemia (JMML)

    Lymphomas Hodgkin's Lymphoma Non-Hodgkin's Lymphoma Burkitt's Lymphoma

    Plasma Cell Disorders Multiple Myeloma Plasma Cell Leukemia Waldenstrom's Macroglobulinemia

    Other cancers (Not originating in the blood system) Neuroblastoma Retinoblastoma

    Inherited Red Cell (Erythrocyte) Abnormalities Beta Thalassemia Major (also known as Cooley's Anemia) Blackfan-Diamond Anemia Pure Red Cell Aplasia Sickle Cell Disease

    Myelodysplastic Syndromes Refractory Anemia (RA) Refractory Anemia with Ringed Sideroblasts (RARS) Refractory Anemia with Excess Blasts (RAEB) Refractory Anemia with Excess Blasts in Transformation (RAEB-T) Chronic Myelomonocytic Leukemia (CMML)

    Other Disorders of Blood Cell Proliferation severe Aplastic Anemia Congenital Dyserythropoietic Anemia Fanconi Anemia (Note: the first cord blood transplant in 1988 was for

    this disease) Paroxysmal Nocturnal Hemoglobinuria (PNH) Pure Red Cell Aplasia Amegakaryocytosis / Congenital Thrombocytopenia Glanzmann Thrombasthenia Acute Myelofibrosis Agnogenic Myeloid Metaplasia (Myelofibrosis) Polycythemia Vera Essential Thrombocythemia

    Inherited Immune System Disorders

    Severe Combined Immunodeficiency (SCID) SCID with Adenosine Deaminase Deficiency (ADA-SCID) SCID which is X-linked SCID with absence of T & B Cells SCID with absence of T Cells, Normal B Cells Omenn Syndrome Neutropenias Kostmann Syndrome Myelokathexis Other Ataxia-Telangiectasia Bare Lymphocyte Syndrome Common Variable Immunodeficiency DiGeorge Syndrome Leukocyte Adhesion Deficiency Lymphoproliferative Disorders (LPD) Lymphoproliferative Disorder, X-linked (also known as Epstein-Barr

    Virus Susceptibility) Wiskott-Aldrich Syndrome Phagocyte Disorders Chediak-Higashi Syndrome Chronic Granulomatous Disease Neutrophil Actin Deficiency Reticular Dysgenesis

    http://www.parentsguidecordblood.org/

  • Current situation in South Africa Bone marrow transplantation (BMT) practiced successfully for many years many South Africans requiring a BMT remain

    untreated

    SA Bone Marrow Registry established in 1991 >65,000 donors registered >250 transplants (matched unrelated donor) Donors: 25% local; 75% international majority of donors are Caucasian

  • Cord blood banking in SA

    Public cord blood bank none at present genetically-diverse population feasibility study

    Mandated by DoH and SANBS Funded by the MRC

    Private cord blood banks 2 in South Africa

  • Application

    Current Bone marrow transplantation Fractures, chronic wounds, burns

    Future Myocardial infarction and heart failure CNS disease (incl. spinal cord injury) Diabetes (beta-cells) Other

  • Future applications

    Nature Medicine 10: 494, 2004

  • Mesenchymal stem cells

    Fat cell

    Myotube

    Osteoblast

    Chrondroblasts

    Sox9

    CBFA1 PPARY

    myo D myogenin

    others

    VEGF

    FGF2

    Endothelial cells

    Elsevier 2005 Adapted from Rodan GA, Harada S, Cell, 1997

  • MSC clinical trials

    ClinicalTrials.gov December 2011

    188 registered MSC clinical trials 80 completed 108 on-going

    Almost 100 new trials initiated in 2010 and 2011 alone

  • Stem cells in SA Stem cell therapy and research are in their

    infancy in South Africa potential to alleviate heavy burden of disease communicable and non-communicable

    Role in cancer, hematological and inherited metabolic disorders well established but unable to meet demand

    Role in heart disease, spinal cord injury and others being assessed globally but not in SA

    Role in infectious diseases totally unexplored

  • Human tissue legislation in South Africa Legislation incomplete and flawed

    increasingly litigious society importance of global standards

    Regulations Redundancy/overlap Lack of regulations

    transplantation cell-based therapy

    Definitions not harmonized (NHA and regulations)

  • Why legislation

    Reason no. 1 To ensure that pre-clinical studies and well

    controlled clinical trials have been conducted prior to introduction of cells into patients to ensure that the purported therapeutic effect

    is real to ensure th